The target area to be studied in this proposal are the molecular targets provided by survival (anti-apoptosis) signaling pathways in cancer cells. We will study six novel cancer drugs that affect these molecular targets. The goal of the work is to develop more effective ways of preventing and treating cancer through a knowledge of the effects of new types of molecular targeted drugs on their specific targets in human cancer. The objectives of the study are to develop specific, sensitive and robust assays for the molecular target, to validate them in cellular and animal models, and to use the assays to measure drug effects on their targets in patient clinical trials. The information obtained from the studies will be used to design more effective clinical trials for molecularly targeted drugs. The overarching hypothesis upon which the study is based is that a pharmacodynamic understanding of the effects of cancer drugs on survival signaling molecular targets in cancer cells will lead to improved ways of using these drugs and more effective therapies for preventing and treating cancer. The program is based upon a specific class of anticancer drugs but the findings should be generally applicable to the development of many classes of molecularly targeted cancer drugs. The work will provide important insights into the way these new types of agents can be developed and how their clinical trial should be conducted.